Abstract Pseudoxanthoma elasticum (PXE) is genetic disorder characterized by degeneration of elastic fibers that leads to dermatologic, ocular and cardiovascular abnormalities, involving progressive calcification of the soft tissues. Calcification can occur within the heart muscle, particularly after injury, and predisposes these patients to cardiac dysfunction or sudden death from ventricular arrhythmias. PXE is caused by mutations in the ATP Binding Cassette C6 transporter gene (ABCC6) yet little is understood how deficiency of ABCC6 induces ectopic calcification in multiple soft tissues. Calcification of soft tissues is thought to be an active process where bone forming osteoblast-like cells are recruited to the affected tissue and cause mineralization of the extracellular matrix, a process analogous to cancellous bone formation. However the nature of the cells contributing to soft tissue calcification in the heart and other organs in PXE and how this is regulated by ABCC6 are unknown. The Deb lab has recently shown that cardiac fibroblasts are not terminally differentiated and presents preliminary data to suggest that fibroblast adopt osteogenic fates and directly contribute to heart muscle calcification in a mouse model of PXE. The Lusis lab was one of the first labs to identify and clone ABCC6 as an important gene regulating soft tissue calcification. In this multi PI proposal, the Deb and Lusis labs interrogate the role of fibroblast plasticity in directly contributing to heart muscle calcification in ABCC6 deficient animals, investigate i) spatio-temporal dynamics of fibroblast-osteoblast transitions ii) biochemical mechanisms regulating fibroblast mediated calcification and ?iii) the physiologic significance of fibroblast mediated calcification. We provide preliminary data that mechanisms regulating calcification in ABCC6 deficiency are dysregulated in other common causes of ectopic calcification such as human heart valve calcification and investigate strategies to inhibit final common pathways mediating ectopic calcification, regardless of the underlying pathology.